Cyclooxygenase-2 inhibitor/histone deacetylase inhibitor combination

ABSTRACT

The invention relates to a combination which comprises (a) a cyclooxygenase-2 inhibitor (“COX-2 inhibitor”) and (b) a histone deacetylase inhibitor (“HDAI”) for simultaneous, concurrent, separate or sequential use, especially for use in the treatment of pre-malignant colon lesions or a colon cancer or other malignancies in a mammal, particularly a human. The invention also relates to pharmaceutical compositions comprising such a combination and to a method of treating pre-malignant colon lesions (e.g. polyps) and colon cancer, as well as other malignancies, in a mammal, particularly a human, with such a combination. The present invention further also relates to a commercial package or product comprising such a combination.

The invention relates to a combination which comprises (a) acyclooxygenase-2 inhibitor (“COX-2 inhibitor”) and (b) a histonedeacetylase inhibitor (“HDAI”) for simultaneous, concurrent, separate orsequential use, especially for use in the treatment of pre-malignantcolon lesions or a colon cancer or other malignancies in a mammal,particularly a human. The invention also relates to pharmaceuticalcompositions comprising such a combination and to a method of treatingpre-malignant colon lesions (e.g. polyps) and colon cancer, as well asother malignancies, in a mammal, particularly a human, with such acombination. The present invention further also relates to a commercialpackage or product comprising such a combination.

The COX-2 inhibitors used in the combination of the present inventionare typically those which have an IC₅₀ for COX-2 inhibition of less thanabout 2 μM and an IC₅₀ for COX-1 inhibition of greater than about 5 μM,e.g. when measured in the assays described by Brideau et al., Inflamm.Res. 45:68-74 (1996). Preferably the COX-2 inhibitor has a selectivityratio of at least 10, more preferably at least 40, for COX-2 inhibitionover COX-1 inhibition.

Of the known COX-2 inhibitors, the 5-alkyl substituted2-arylaminophenylacetic acids and derivatives are especially useful inthe present invention. Such compounds, their use and preparation aredisclosed in U.S. Pat. No. 6,291,523 and are herein incorporated byreference.

Useful COX-2 inhibitors disclosed in U.S. Pat. No. 6,291,523 aredescribed by formula Ia

wherein R* is methyl or ethyl;

-   -   R*₁ is chloro or fluoro;    -   R*₂ is hydrogen or fluoro;    -   R*₃ is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy        or hydroxy;    -   R*₄ is hydrogen or fluoro; and    -   R*₅ is chloro, fluoro, trifluoromethyl or methyl;    -   pharmaceutically acceptable salts or solvates thereof; and    -   pharmaceutically acceptable prodrug esters thereof.

A particular embodiment of the invention relates to the compounds offormula Ia wherein R* is methyl or ethyl; R*₁ is chloro or fluoro; R*₂is hydrogen; R*₃ is hydrogen, fluoro, chloro, methyl or hydroxy; R*₄ ishydrogen; and R*₅ is chloro, fluoro or methyl; pharmaceuticallyacceptable salts thereof; and pharmaceutically acceptable prodrug estersthereof.

A preferred embodiment relates to the compounds of formula Ia wherein R*is methyl or ethyl; R*₁ is fluoro; R*₂ is hydrogen; R*₃ is hydrogen,fluoro or hydroxy; R*₄ is hydrogen; and R*₅ is chloro; pharmaceuticallyacceptable salts thereof; and pharmaceutically acceptable prodrug estersthereof.

Another preferred embodiment of the invention relates to compound offormula Ia wherein R* is ethyl or methyl; R*₁ is fluoro; R*₂ is hydrogenor fluoro; R*₃ is hydrogen, fluoro, ethoxy or hydroxy; R*₄ is hydrogenor fluoro; and R*₅ is chloro, fluoro or methyl; pharmaceuticallyacceptable salts thereof; and pharmaceutically acceptable prodrug estersthereof.

Further preferred are said compounds wherein R* is methyl or ethyl; R*₁is fluoro; R*₂-R*₄ are hydrogen or fluoro; and R*₅ is chloro or fluoro;pharmaceutically acceptable salts thereof; and pharmaceuticallyacceptable prodrug esters thereof.

A further embodiment of the invention relates to the compounds offormula Ia wherein R* is methyl or ethyl; R*₅, is fluoro; R*₂ is fluoro;R*₃ is hydrogen, ethoxy or hydroxy; R*₄ is fluoro; and R*₅ is fluoro;pharmaceutically acceptable salts thereof; and pharmaceuticallyacceptable prodrug esters thereof.

Another preferred embodiment of the invention relates to the compoundsof formula Ia wherein R* is methyl; R*₁ is fluoro; R*₂ is hydrogen; R*₃is hydrogen or fluoro; R*₄ is hydrogen; and R*₅ is chloro;pharmaceutically acceptable salts thereof; and pharmaceuticallyacceptable prodrug esters thereof.

Particular embodiments of the invention relate to compounds of formulaIa

-   -   (a) wherein R* is methyl; R*₁ is fluoro; R*₂ is hydrogen; R*₃ is        hydrogen; R*₄ is hydrogen; and R*₅ is chloro; pharmaceutically        acceptable salts thereof; and pharmaceutically acceptable        prodrug esters thereof;    -   (b) wherein R* is methyl; R*₁ is fluoro; R*₂ is hydrogen; R*₃ is        fluoro; R*₄ is hydrogen; and R*₅ is chloro; pharmaceutically        acceptable salts thereof; and pharmaceutically acceptable        prodrug esters thereof;    -   (c) wherein R* is ethyl; R*₁ is fluoro; R*₂ is fluoro; R*₃ is        hydrogen; R*₄ is fluoro; and R*₅ is fluoro; pharmaceutically        acceptable salts thereof; and pharmaceutically acceptable        prodrug esters thereof; and    -   (d) wherein R* is ethyl; R*₁ is chloro; R*₂ is hydrogen; R*₃ is        chloro; R*₄ is hydrogen; and R*₅ is methyl; pharmaceutically        acceptable salts thereof; and pharmaceutically acceptable        prodrug esters thereof.

Pharmaceutically acceptable prodrug esters are ester derivatives whichare convertible by solvolysis or under physiological conditions to thefree carboxylic acids of formula Ia. Such esters are e.g. lower alkylesters (such as the methyl or ethyl ester), carboxy-lower alkyl esterssuch as the carboxymethyl ester, nitrooxy-lower alkyl esters (such asthe 4-nitrooxybutyl ester), and the like. Preferred are the 5-alkylsubstituted 2-arylaminophenylacetoxyacetic acids of formula Ib

wherein R* and R*₁-R*₅ have meaning as defined hereinabove for compoundsof formula Ia; and pharmaceutically acceptable salts thereof.

Thus, COX-2 inhibitors useful for use in the present invention arecompounds of formula I

wherein R* is methyl or ethyl;

-   -   R*₁ is chloro or fluoro;    -   R*₂ is hydrogen or fluoro;    -   R*₃ is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy        or hydroxy;    -   R*₄ is hydrogen or fluoro;    -   R*₅ is chloro, fluoro, trifluoromethyl or methyl; and    -   R*₆ is hydroxy or —OCH₂COOH;        pharmaceutically acceptable salts or solvates thereof; and        pharmaceutically acceptable prodrug esters thereof.

Pharmaceutically acceptable salts represent metal salts, such asalkaline metal salts, e.g. sodium, potassium, magnesium or calciumsalts, as well as ammonium salts, which are formed e.g. with ammonia andmono- or di-alkylamines, such as diethylammonium salts, and with aminoacids, such as arginine and histidine salts.

The compound 5-methyl-2-(2′-chloro-6′-fluoro-anilino)-phenyl aceticacid, as well as its pharmaceutically acceptable salts, is an especiallyuseful COX-2 inhibitor for use in the present invention.

Also useful in the practice of the invention are the followingCOX-2-inhibiting compounds, derivatives thereof, or pharmaceuticallyacceptable salts thereof, or any hydrate thereof: rofecoxib, etoricoxib,celecoxib, valdecoxib, and parecoxib.

Another class of COX-2 inhibitors compounds for use in the invention isthe methane sulfonanilide class of inhibitors, of which NS-398,flosulide, nimesulide and (i) are example members.

A further class of COX-2 inhibitors useful in the practice of thepresent invention is the tricyclic inhibitor class, which can be furtherdivided into the sub-classes of tricyclic inhibitors with a centralcarbocyclic ring (examples include SC-57666, 1 and 2; those with acentral monocyclic heterocyclic ring (examples include DuP697, SC-58125,SC-58635, SC-236 and 3, 4 and 5); and those with a central bicyclicheterocyclic ring (examples include 6, 7, 8, 9 and 10). Compounds 3, 4,and 5 are described in U.S. Pat. No. 5,474,995. The structure of theactive agents identified hereinbefore or hereinafter by code nos.,generic or trade names may be taken from the actual edition of thestandard compendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

A yet further class of COX-2 inhibitors can be referred to as thosewhich are structurally modified nonsteroidal antiinflammatory drugs(NSAIDs), and includes 11a and structure 11b as exemplary members. Thesynthesis of compound 11b is described in U.S. Pat. No. 5,622,948.

In addition to these structural classes, sub-classes, and specific COX-2inhibitor compound examples, examples of compounds which selectivelyinhibit cyclooxygenase-2 have also been described in the followingpatent publications and are herein incorporated by reference: U.S. Pat.Nos. 5,344,991, 5,380,738, 5,393,790, 5,409,944, 5,434,178, 5,436,265,5,466,823, 5,474,995, 5,510,368, 5,536,752, 5,550,142, 5,552,422,5,604,253, 5,604,260, 5,639,780; and International Patent SpecificationNos. 94/13635, 94/15932, 94/20480, 94/26731, 94/27980, 95/00501,95/15316, 96/03387, 96/03388, 96/06840; and International PublicationNo.'s WO 94/20480, WO 96/21667, WO 96/31509, WO 96/36623, WO 97/14691,WO 97/16435.

Additional COX-2 inhibitor compounds, the use of which are included inthe scope of this invention, include:

Some of the compounds above can also be identified by the followingchemical names:

-   3: 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone;-   4:    3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-faranone;-   5:    5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-3-(3-fluorophenyl)-H-furan-2-one;-   12:    5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-3-(2-propoxy)-5H-furan-2-one;-   13:    5-chloro-3-(4-(methylsulfonyl)phenyl)-2-(2-methyl-5-pyridinyl)pyridine;-   14:    2-(3,5-difluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one;-   15:    5(S)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl)-3-(2-propoxy)-5H-furan-2-one;-   16:    5-ethyl-5-methyl-4-(4-(methylsulfonyl)phenyl)-3-(3,4-difluorophenyl)-5H-furan-2-one;-   17:    3-((2-thiazolyl)methoxy)-4-(4-methylsulfonyl)phenyl)-5,5-dymethyl-5H-furan-2-one;-   18:    3-propyloxy-4-(4-methylsulfonyl)phenyl)-5,5-dimethyl-5H-furan-2-one;-   19:    3-(1-cyclopropylethoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl)-5H-furan-2-one;-   20: sodium    2-(4-chlorophenyl)-3-(4-methylsulfonyl)phenyl)-4-oxo-2-pentenoate;-   21:    3-(cyclopropylmethoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl)-5H-furan-2-one;-   22:    3-(cyclopropylmethoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl)-2,5-dihydrofuran-2-ol;-   23:    3-isopropoxy-5,5-dimethyl-4-(4-methylsulfonyl)phenyl)-2,5-dihydrofuran-2-ol;-   24:    5,5-dimethyl-3-(3-fluorophenyl)-2-hydroxy-4-(4-methylsulfonyl)phenyl)-2,5-dihydrofuran;-   25: 5-Chloro-3-(4-methylsulfonyl)phenyl)-2-(3-pyridinyl)pyridine.

The following publications describe and/or provide methods for makingthe compounds as indicated: compounds 12, 15, 17, 18, 19 and 21, WO97/14691; compounds 22, 23 and 24, WO 97/16435; compound 20, WO96/36623; compound 14, U.S. Pat. No. 5,536,752; compound 16, U.S. Pat.No. 5,474,995; compounds 13 and 25, WO 98/03484. Also incorporatedherein by reference are those compounds described in WO 96/41645 ashaving structural formula III, shown below, and the definition andpreferred definitions and species described therein:

Particularly preferred compounds of formula (III) include:

-   5-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole;-   4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-1-phenyl-3-(trifluoromethyl)pyrazole;-   4-(5-(4-chlorophenyl)-3-(4-methodoxyphenyl)-1H-pyrazol-1-yl)benzenesulfonamide;-   4-(3,5-bis(4-methylphenyl)-1H-pyrazol-1-yl)benzenesulfonamide;-   4-(5-(4-chlorophenyl)-3-phenyl-1H-pyrazol-1-yl)benzenesulfonamide;-   4-(3,5-bis(4-methoxyphenyl)-1H-pyrazol-1-yl)benzenesulfonamide;-   4-(5-(4-chlorophenyl)-3-(4-methylphenyl)-1H-pyrazol-1-yl)benzenesulfonamide;-   4-(5-(4-chlorophenyl)-3-(4-nitrophenyl)-1H-pyrazol-1-yl)benzenesulfonamide;-   4-(5-(4-chlorophenyl)-3-(5-chloro-2-thienyl)-1H-pyrazol-1-yl)benzenesulfonamide;-   4-(4-chloro-3,5-diphenyl-1H-pyrazol-1-yl)benzenesulfonamide;-   4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide;-   4-(5-phenyl)-3-(trifluormethyl)-1H-pyrazol-1-yl)benzenesulfonamide;-   4-(5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide;-   4-(5-(4-methoxyphenyl)-3-(trifluormethyl)-1H-pyrazol-1-yl)benzenesulfonamide;-   4-(5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide;-   4-(5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide;-   4-(4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide;-   4-(3-(difluoromethyl)-5-(4-methylphenyl)-1H-pyrazol-1-yl)benzenesulfonamide;-   4-(3-(difluoromethyl)-5-phenyl-1H-pyrazol-1-yl)benzenesulfonamide;-   4-(3-(difluoromethyl)-5-(4-methoxyphenyl)-1H-pyrazol-1-yl)benzenesulfonamide;-   4-(3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl)benzenesulfonamide;-   4-(3-(difluoromethyl)-5-(3-fluoro-4-methodoxyphenyl)-1H-pyrazol-1-yl)benzenesulfonamide;-   4-(5-(3-fluoro-4-methoxyphenyl)-3-(trifluormethyl)-1H-pyrazol-1-yl)benzenesulfonamide;-   4-(4-chloro-5-phenyl-1H-pyrazol-1-yl)benzenesulfonamide;-   4-(5-(4-chlorophenyl)-3-hydroxyphenyl)-1H-pyrazol-1-yl)benzenesulfonamide;-   4-(5-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide;-   5-(4-fluorophenyl)-6-(4-(methylsulfonyl)phenyl)spiro[2.4]hept-5-ene;-   4-(6-(4-fluorophenyl)spiro[2.4]hept-5-en-5-yl)benzenesulfonamide;-   6-(4-fluorophenyl)-7-(4-(methylsulfonyl)phenyl)spiro[3.4]oct-6-ene;-   5-(3-chloro-4-methoxyphenyl)-6-(4-(methylsulfonyl)phenyl)spiro[2.4]hept-5-ene;-   4-(6-(3-chloro-4-methoxyphenyl)spiro[2.4]hept-5-en-5-yl)benzenesulfonamide;-   5-(3,5-dichloro-4-methodoxyphenyl)-6-(4-(methylsulfonyl)phenyl)spiro[2.4]hept-5-ene;-   5-(3-chloro-4-fluorophenyl)-6-(4-(methylsulfonyl)phenyl)spiro[2.4]hept-5-ene;-   4-(6-(3,4-dichlorophenyl)spiro[2.4]hept-5-en-5-yl)benzenesulfonamide;-   2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)thiazole;-   2-(2-chlorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)thiazole;-   5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-methylthiazole;-   4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-trifluormethylthiazole;-   4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(2-thienyl)thiazole;-   4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-benzenesulfonamide;-   4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(1-propylamino)thiazole;-   2-((3,5-dichlorophenoxy)methyl)-4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)thiazole;-   5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethylthiazole;-   1-methylsulfonyl-4-(1,1-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien-3-yl)benzene;-   4-(4-(4-fluorophenyl-1,1-dimethylcyclopenta-2,4-dien-3-yl)benzenesulfonamide;-   5-(4-fluorophenyl)-6-(4-(methylsulfonyl)phenyl)spiro[2.4]hepta-4,6-diene;-   4-(6-(4-fluorophenyl)spiro[2.4]hepta-4,6-dien-5-yl)benzenesulfonamide;-   6-(4-fluorophenyl)-2-methoxy-5-(4-(methylsulfonyl)phenyl)-pyridine-3-carbonitrile;-   2-bromo-6-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-pyridine-3-carbonitrile;-   6-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-2-phenyl-pyridine-3-carbonitrile;-   4-(2-(4-methylpyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl)benzenesulfonamide;-   4-(2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl)benzenesulfonamide;-   4-(2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl)benzenesulfonamide;-   3-(1-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzenesulfonamide;-   2-(1-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine;-   2-methyl-4-(1-(4-(methylsulfonyl)phenyl)-4-(trifluormethyl)-1H-imidazol-2-yl)pyridine;-   2-methyl-6-(1-(4-(methylsulfonyl)phenyl)-4-(trifluormethyl)-1H-imidazole-2-yl)pyridine;-   4-(2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl)benzenesulfonamide;-   2-(3,4-difluorophenyl)-1-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-imidazole;-   4-(2-(4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)benzesulfonamide;-   2-(4-chlorophenyl)-1-(4-methylsulfonyl)phenyl)-4-methyl-1H-imidazole;-   2-(4-chlorophenyl)-1-(4-(methylsulfonyl)phenyl)-4-phenyl-1H-imidazole;-   2-(4-chlorophenyl)-4-(4-fluorophenyl)-1-(4-(methylsulfonyl)phenyl)-1H-imidazole;-   2-(3-fluoro-4-methoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-imidazole;-   1-(4-methylsulfonyl)phenyl)-2-phenyl-4-trifluoromethyl-1H-imidazole;-   2-(4-methylphenyl)-1-(4-(methylsulfonyl)phenyl)-4-trifluoromethyl-1H-imidazole;-   4-(2-(3-chloro-4-methylphenyl)-4-(trifluoromethyl-1H-imidazol-1-yl)benzenesulfonamide;-   2-(3-fluoro-5-methylphenyl)-1-(4-methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-imidazole;-   4-(2-(3-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)benzenesulfonamide;-   2-(3-methylphenyl)-1-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-imidazole;-   4-(2-(3-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)benzenesulfonamide;-   1-(4-(methylsulfonyl)phenyl)-2-(3-chlorophenyl)-4-(trifluoromethyl)-1H-imidazole;-   4-(2-(3-chlorophenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)benzenesulfonamide;-   4-(2-phenyl-4-(trifluoromethyl)-1H-imidazol-1-yl)benzenesulfonamide;-   4-(2-(4-methoxy-3-chlorophenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)benzenesulfonamide-   1-allyl-4-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-5-(trifluoromethyl)-1H-pyrazole;-   4-(1-ethyl-4-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)benzenesulfonamide;-   N-phenyl-(4-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide;-   ethyl    (4-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)acetate;-   4-(4-fluorophenyl)-3-(4-methylsulfonyl)phenyl)-1-(2-phenylethyl)-1H-pyrazole;-   4-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-1-(2-phenylethyl)-5-(trifluoromethyl)pyrazole;-   1-ethyl-4-(4-fluorophenyl)-3-(4-methylsulfonyl)phenyl)-5-(trifluoromethyl)-H-pyrazole;-   5-(4-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(trifluoromethyl)-1H-imidazole;-   4-(4-methylsulfonyl)phenyl)-5-(2-thiophenyl)-2-(trifluoromethyl)-1H-imidazole;-   5-(4-fluorophenyl)-2-methodoxy-4-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridine;-   2-ethoxy-5-(4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridine;-   5-(4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(2-propynyloxy)-6-(trifluoromethyl)pyridine;-   2-bromo-5-(4-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridine;-   4-(2-(3-chloro-4-methoxyphenyl)-4,5-difluorophenyl)benzensulfonamide;-   1-(4-fluorophenyl)-2-(4-methylsulfonyl)phenyl)benzene;-   5-difluoromethyl-4-(4-methylsulfonyl)phenyl)-3-phenylisoxazole;-   4-(3-ethyl-5-phenylisoxazol-4-yl)benzensulfonamide;-   4-(5-difluoromethyl-3-phenylisoxazol-4-yl)benzenesulfonamide;-   4-(5-hydroxymethyl-3-phenylisoxazol-4-yl)benzenesulfonamide;-   4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide;-   1-(2-(4-fluorophenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene;-   1-(2-(4-fluoro-2-methylphenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene;-   1-(2-(4-chlorophenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene;-   1-(2-(2,4-dichlorophenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene;-   1-(2-(4-trifluoromethylphenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene;-   1-(2-(4-methylthiophenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene;-   1-(2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl)-4-(methylsulfonyl)benzene;-   4-(2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl)benzesulfonamide;-   1-(2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl)-4-(methylsulfonyl)benzene;-   4-(2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl)benzenesulfonamide;-   4-(2-(4-fluorophenyl)cyclopenten-1-yl)benzenesulfonamide;-   4-(2-(4-chlorophenyl)cyclopenten-1-yl)benzenesulfonamide;-   1-(2-(4-methoxyphenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene;-   1-(2-(2,3-difluorophenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene;-   4-(2-(3-fluoro-4-methoxyphenyl)cyclopenten-1-yl)benzenesulfonamide;-   1-(2-(3-chloro-4-methoxyphenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene;-   4-(2-(3-chloro-4-fluorophenyl)cyclopenten-1-yl-benzenesulfonamide;-   4-(2-(2-methylpyridin-5-yl)cyclopenten-1-yl)benzenesulfonamide;-   ethyl    2-(4-(4-fluorophenyl)-5-(4-methylsulfonyl)phenyl)oxazol-2-yl)-2-benzyl-acetate;-   2-(4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)oxazol-2-yl)acetic    acid;-   2-(tert-butyl)-4-(4-fluorophenyl)-5-(4-methylsulfonyl)phenyl)oxazole;-   4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-2-phenyloxazole;-   4-(4-fluorophenyl)-2-methyl-5-(4-methylsulfonyl)phenyl)oxazole; and-   4-(5-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4-oxazolyl)benzenesulfonamide;    or a pharmaceutically acceptable salt thereof.

HDAI compounds that are of particular interest for use in thecombinations and methods of the invention are hydroxamate compoundsdescribed by the formula II

wherein

-   -   R₁ is H, halo, or a straight chain C₁-C₆ alkyl (especially        methyl, ethyl or n-propyl, which methyl, ethyl and n-propyl        substituents are unsubstituted or substituted by one or more        substituents described below for alkyl substituents);    -   R₂ is selected from H, C₁-C₁₀ alkyl, (preferably C₁-C₆ alkyl,        e.g. methyl, ethyl or —CH₂CH₂—OH), C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, C₄-C₉ heterocycloalkylalkyl, cycloalkylalkyl        (e.g., cyclopropylmethyl), aryl, heteroaryl, arylalkyl (e.g.        benzyl), heteroarylalkyl (e.g. pyridylmethyl), —(CH₂)_(n)C(O)R₆,        —(CH₂)_(n)OC(O)R₆, amino acyl, HON—C(O)—CH═C(R₁)-aryl-alkyl- and        —(CH₂)_(n)R₇;    -   R₃ and R₄ are the same or different and independently H, C₁-C₆        alkyl, acyl or acylamino, or R₃ and R₄ together with the carbon        to which they are bound represent C═O, C═S, or C═NR₈, or R₂        together with the nitrogen to which it is bound and R₃ together        with the carbon to which it is bound can form a C₄-C₉        heterocycloalkyl, a heteroaryl, a polyheteroaryl, a non-aromatic        polyheterocycle, or a mixed aryl and non-aryl polyheterocycle        ring;    -   R₅ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, acyl, aryl, heteroaryl, arylalkyl (e.g.        benzyl), heteroarylalkyl (e.g. pyridylmethyl), aromatic        polycycles, non-aromatic polycycles, mixed aryl and non-aryl        polycycles, polyheteroaryl, non-aromatic polyheterocycles, and        mixed aryl and non-aryl polyheterocycles;    -   n, n₁, n₂ and n₃ are the same or different and independently        selected from 0-6, when n₁ is 1-6, each carbon atom can be        optionally and independently substituted with R₃ and/or R₄;    -   X and Y are the same or different and independently selected        from H, halo, C₁-C₄ alkyl, such as CH₃ and CF₃, NO₂, C(O)R₁,        OR₉, SR₉, CN, and NR₁₀R₁₁;    -   R₆ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl),        aryl, heteroaryl, arylalkyl (e.g., benzyl, 2-phenylethenyl),        heteroarylalkyl (e.g., pyridylmethyl), OR₁₂, and NR₁₃R₁₄;    -   R₇ is selected from OR₁₅, SR₁₅, S(O)R₁₆, SO₂R₁₇, NR₁₃R₁₄, and        NR₁₂SO₂R₆;    -   R₈ is selected from H, OR₁₅, NR₁₃R₁₄, C₁-C₆ alkyl, C₄-C₉        cycloalkyl, C₄-C₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl        (e.g., benzyl), and heteroarylalkyl (e.g., pyridylmethyl);    -   R₉ is selected from C₁-C₄ alkyl, for example, CH₃ and CF₃,        C(O)-alkyl, for example C(O)CH₃, and C(O)CF₃;    -   R₁₀ and R₁₁ are the same or different and independently selected        from H, C₁-C₄ alkyl, and —C(O)-alkyl;    -   R₁₂ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, C₄-C₉ heterocycloalkylalkyl, aryl, mixed aryl        and non-aryl polycycle, heteroaryl, arylalkyl (e.g., benzyl),        and heteroarylalkyl (e.g., pyridylmethyl);    -   R₁₃ and R₁₄ are the same or different and independently selected        from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,        aryl, heteroaryl, arylalkyl (e.g., benzyl), heteroarylalkyl        (e.g., pyridylmethyl), amino acyl, or R₁₃ and R₁₄ together with        the nitrogen to which they are bound are C₄-C₉ heterocycloalkyl,        heteroaryl, polyheteroaryl, non-aromatic polyheterocycle or        mixed aryl and non-aryl polyheterocycle;    -   R₁₅ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl        and (CH₂)_(m)ZR₁₂;    -   R₁₆ is selected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, aryl, heteroaryl, polyheteroaryl, arylalkyl,        heteroarylalkyl and (CH₂)_(m)ZR₁₂;    -   R₁₇ is selected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, aryl, aromatic polycycles, heteroaryl,        arylalkyl, heteroarylalkyl, polyheteroaryl and NR₁₃R₁₄;    -   m is an integer selected from 0 to 6; and    -   Z is selected from O, NR₁₃, S and S(O),        or a pharmaceutically acceptable salt thereof.

As appropriate, unsubstituted means that there is no substituent or thatthe only substituents are hydrogen.

Halo substituents are selected from fluoro, chloro, bromo and iodo,preferably fluoro or chloro.

Alkyl substituents include straight and branched C₁-C₆alkyl, unlessotherwise noted. Examples of suitable straight and branched C₁-C₆alkylsubstituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl,sec-butyl, t-butyl, and the like. Unless otherwise noted, the alkylsubstituents include both unsubstituted alkyl groups and alkyl groupsthat are substituted by one or more suitable substituents, includingunsaturation (i.e. there are one or more double or triple C—C bonds),acyl, cycloalkyl, halo, oxyalkyl, alkylamino, aminoalkyl, acylamino andOR₁₅, for example, alkoxy. Preferred substituents for alkyl groupsinclude halo, hydroxy, alkoxy, oxyalkyl, alkylamino, and aminoalkyl.

Cycloalkyl substituents include C₃-C₉ cycloalkyl groups, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unlessotherwise specified. Unless otherwise noted, cycloalkyl substituentsinclude both unsubstituted cycloalkyl groups and cycloalkyl groups thatare substituted by one or more suitable substituents, including C₁-C₆alkyl, halo, hydroxy, aminoalkyl, oxyalkyl, alkylamino, and OR₁₅, suchas alkoxy. Preferred substituents for cycloalkyl groups include halo,hydroxy, alkoxy, oxyalkyl, alkylamino and aminoalkyl.

The above discussion of alkyl and cycloalkyl substituents also appliesto the alkyl portions of other substituents, such as without limitation,alkoxy, alkyl amines, alkyl ketones, arylalkyl, heteroarylalkyl,alkylsulfonyl and alkyl ester substituents and the like.

Heterocycloalkyl substituents include 3 to 9 membered aliphatic rings,such as 4 to 7 membered aliphatic rings, containing from one to threeheteroatoms selected from nitrogen, sulfur, oxygen. Examples of suitableheterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl,tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl,morphilino, 1,3-diazapane, 1,4-diazapane, 1,4-oxazepane, and1,4-oxathiapane. Unless otherwise noted, the rings are unsubstituted orsubstituted on the carbon atoms by one or more suitable substituents,including C₁-C₆ alkyl, C₄-C₉ cycloalkyl, aryl, heteroaryl, arylalkyl(e.g., benzyl), and heteroarylalkyl (e.g., pyridylmethyl), halo, amino,alkyl amino and OR₁₅, for example alkoxy. Unless otherwise noted,nitrogen heteroatoms are unsubstituted or substituted by H, C₁-C₄ alkyl,arylalkyl (e.g., benzyl), and heteroarylalkyl (e.g., pyridylmethyl),acyl, aminoacyl, alkylsulfonyl, and arylsulfonyl.

Cycloalkylalkyl substituents include compounds of the formula—(CH₂)_(n5)-cycloalkyl wherein n5 is a number from 1-6. Suitablealkylcycloalkyl substituents include cyclopentylmethyl-,cyclopentylethyl, cyclohexylmethyl and the like. Such substituents areunsubstituted or substituted in the alkyl portion or in the cycloalkylportion by a suitable substituent, including those listed above foralkyl and cycloalkyl.

Aryl substituents include unsubstituted phenyl and phenyl substituted byone or more suitable substituents, including C₁-C₆ alkyl,cycloalkylalkyl (e.g., cyclopropylmethyl), O(CO)alkyl, oxyalkyl, halo,nitro, amino, alkylamino, aminoalkyl, alkyl ketones, nitrile,carboxyalkyl, alkylsulfonyl, aminosulfonyl, arylsulfonyl, and OR₁₅, suchas alkoxy. Preferred substituents include including C₁-C₆ alkyl,cycloalkyl (e.g., cyclopropylmethyl), alkoxy, oxyalkyl, halo, nitro,amino, alkylamino, aminoalkyl, alkyl ketones, nitrile, carboxyalkyl,alkylsulfonyl, arylsulfonyl, and aminosulfonyl. Examples of suitablearyl groups include C₁-C₄alkylphenyl, C₁-C₄alkoxyphenyl,trifluoromethylphenyl, methoxyphenyl, hydroxyethylphenyl,dimethylaminophenyl, aminopropylphenyl, carbethoxyphenyl,methanesulfonylphenyl and tolylsulfonylphenyl.

Aromatic polycycles include naphthyl, and naphthyl substituted by one ormore suitable substituents, including C₁-C₆ alkyl, alkylcycloalkyl(e.g., cyclopropylmethyl), oxyalkyl, halo, nitro, amino, alkylamino,aminoalkyl, alkyl ketones, nitrile, carboxyalkyl, alkylsulfonyl,arylsulfonyl, aminosulfonyl and OR₁₅, such as alkoxy.

Heteroaryl substituents include compounds with a 5 to 7 member aromaticring containing one or more heteroatoms, for example from 1 to 4heteroatoms, selected from N, O and S. Typical heteroaryl substituentsinclude furyl, thienyl, pyrrole, pyrazole, triazole, thiazole, oxazole,pyridine, pyrimidine, isoxazolyl, pyrazine and the like. Unlessotherwise noted, heteroaryl substituents are unsubstituted orsubstituted on a carbon atom by one or more suitable substituents,including alkyl, the alkyl substituents identified above, and anotherheteroaryl substituent. Nitrogen atoms are unsubstituted or substituted,for example by R₁₃; especially useful N substituents include H, C₁-C₄alkyl, acyl, aminoacyl, and sulfonyl.

Arylalkyl substituents include groups of the formula —(CH₂)_(n5)-aryl,—(CH₂)_(n5-1)—(CHaryl)-(CH₂)_(n5)-aryl or —(CH₂)_(n5-1)CH(aryl)(aryl)wherein aryl and n5 are defined above. Such arylalkyl substituentsinclude benzyl, 2-phenylethyl, 1-phenylethyl, tolyl-3-propyl,2-phenylpropyl, diphenylmethyl, 2-diphenylethyl,5,5-dimethyl-3-phenylpentyl and the like. Arylalkyl substituents areunsubstituted or substituted in the alkyl moiety or the aryl moiety orboth as described above for alkyl and aryl substituents.

Heteroarylalkyl substituents include groups of the formula—(CH₂)_(n5)-heteroaryl wherein heteroaryl and n5 are defined above andthe bridging group is linked to a carbon or a nitrogen of the heteroarylportion, such as 2-, 3- or 4-pyridylmethyl, imidazolylmethyl,quinolylethyl, and pyrrolylbutyl. Heteroaryl substituents areunsubstituted or substituted as discussed above for heteroaryl and alkylsubstituents.

Amino acyl substituents include groups of the formula—C(O)—(CH₂)_(n)—C(H)(NR₁₃R₁₄)—(CH₂)_(n)—R₅ wherein n, R₁₃, R₁₄ and R₅are described above. Suitable aminoacyl substituents include natural andnon-natural amino acids such as glycinyl, D-tryptophanyl, L-lysinyl, D-or L-homoserinyl, 4-aminobutryic acyl, ±3-amin-4-hexenoyl.

Non-aromatic polycycle substituents include bicyclic and tricyclic fusedring systems where each ring can be 4-9 membered and each ring cancontain zero, 1 or more double and/or triple bonds. Suitable examples ofnon-aromatic polycycles include decalin, octahydroindene,perhydrobenzocycloheptene, perhydrobenzo-[f]-azulene. Such substituentsare unsubstituted or substituted as described above for cycloalkylgroups.

Mixed aryl and non-aryl polycycle substituents include bicyclic andtricyclic fused ring systems where each ring can be 4-9 membered and atleast one ring is aromatic. Suitable examples of mixed aryl and non-arylpolycycles include methylenedioxyphenyl, bis-methylenedioxyphenyl,1,2,3,4-tetrahydronaphthalene, dibenzosuberane, dihdydroanthracene,9H-fluorene. Such substituents are unsubstituted or substituted by nitroor as described above for cycloalkyl groups.

Polyheteroaryl substituents include bicyclic and tricyclic fused ringsystems where each ring can independently be 5 or 6 membered and containone or more heteroatom, for example, 1, 2, 3, or 4 heteroatoms, chosenfrom O, N or S such that the fused ring system is aromatic. Suitableexamples of polyheteroaryl ring systems include quinoline, isoquinoline,pyridopyrazine, pyrrolopyridine, furopyridine, indole, benzofuran,benzothiofuran, benzindole, benzoxazole, pyrroloquinoline, and the like.Unless otherwise noted, polyheteroaryl substituents are unsubstituted orsubstituted on a carbon atom by one or more suitable substituents,including alkyl, the alkyl substituents identified above and asubstituent of the formula —O—(CH₂CH═CH(CH₃)(CH₂))₁₋₃H. Nitrogen atomsare unsubstituted or substituted, for example by R₁₃; especially usefulN substituents include H, C₁-C₄ alkyl, acyl, aminoacyl, and sulfonyl.

Non-aromatic polyheterocyclic substituents include bicyclic andtricyclic fused ring systems where each ring can be 4-9 membered,contain one or more heteroatom, for example, 1, 2, 3, or 4 heteroatoms,chosen from O, N or S and contain zero or one or more C—C double ortriple bonds. Suitable examples of non-aromatic polyheterocycles includehexitol, cis-perhydro-cyclohepta[b]pyridinyl,decahydro-benzo[f][1,4]oxazepinyl, 2,8-dioxabicyclo[3.3.0]octane,hexahydro-thieno[3,2-b]thiophene, perhydropyrrolo[3,2-b]pyrrole,perhydronaphthyridine, perhydro-1H-dicyclopenta[b,e]pyran. Unlessotherwise noted, non-aromatic polyheterocyclic substituents areunsubstituted or substituted on a carbon atom by one or moresubstituents, including alkyl and the alkyl substituents identifiedabove. Nitrogen atoms are unsubstituted or substituted, for example, byR₁₃; especially useful N substituents include H, C₁-C₄ alkyl, acyl,aminoacyl, and sulfonyl.

Mixed aryl and non-aryl polyheterocycles substituents include bicyclicand tricyclic fused ring systems where each ring can be 4-9 membered,contain one or more heteroatom chosen from O, N or S, and at least oneof the rings must be aromatic. Suitable examples of mixed aryl andnon-aryl polyheterocycles include 2,3-dihydroindole,1,2,3,4-tetrahydroquinoline, 5,11-dihydro-10H-dibenz[b,e][1,4]diazepine,5H-dibenzo[b,e][1,4]diazepine,1,2-dihydropyrrolo[3,4-b][1,5]benzodiazepine,1,5-dihydro-pyrido[2,3-b][1,4]diazepin-4-one,1,2,3,4,6,11-hexahydro-benzo[b]pyrido[2,3-e][1,4]diazepin-5-one. Unlessotherwise noted, mixed aryl and non-aryl polyheterocyclic substituentsare unsubstituted or substituted on a carbon atom by one or moresuitable substituents, including, —N—OH, ═N—OH, alkyl and the alkylsubstituents identified above. Nitrogen atoms are unsubstituted orsubstituted, for example, by R₁₃; especially useful N substituentsinclude H, C₁-C₄ alkyl, acyl, aminoacyl, and sulfonyl.

Amino substituents include primary, secondary and tertiary amines and insalt form, quaternary amines. Examples of amino substituents includemono- and di-alkylamino, mono- and di-aryl amino, mono- and di-arylalkylamino, aryl-arylalkylamino, alkyl-arylamino, alkyl-arylalkylamino andthe like.

Sulfonyl substituents include alkylsulfonyl and arylsulfonyl, forexample methane sulfonyl, benzene sulfonyl, tosyl and the like.

Acyl substituents include groups of formula —C(O)—W, —OC(O)—W, —C(O)—O—Wor —C(O)NR₁₃R₁₄, where W is R₁₆, H or cycloalkylalkyl.

Acylamino substituents include substituents of the formula—N(R₁₂)C(O)—W, —N(R₁₂)C(O)—O—W, and —N(R₁₂)C(O)—NHOH and R₁₂ and W aredefined above.

The R₂ substituent HON—C(O)—CH═C(R₁)-aryl-alkyl- is a group of theformula

Preferences for each of the substituents include the following:

-   -   R₁ is H, halo, or a straight chain C₁-C₄ alkyl;    -   R₂ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl,        heteroarylalkyl, —(CH₂)_(n)C(O)R₆, amino acyl, and —(CH₂)_(n)R₇;    -   R₃ and R₄ are the same or different and independently selected        from H, and C₁-C₆ alkyl, or R₃ and R₄ together with the carbon        to which they are bound represent C═O, C═S, or C═NR₈;    -   R₅ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,        a aromatic polycycle, a non-aromatic polycycle, a mixed aryl and        non-aryl polycycle, polyheteroaryl, a non-aromatic        polyheterocycle, and a mixed aryl and non-aryl polyheterocycle;    -   n, n₁, n₂ and n₃ are the same or different and independently        selected from 0-6, when n₁ , is 1-6, each carbon atom is        unsubstituted or independently substituted with R₃ and/or R₄;    -   X and Y are the same or different and independently selected        from H, halo, C₁-C₄ alkyl, CF₃, NO₂, C(O)R₁, OR₉, SR₉, CN, and        NR₁₀R₁₁;    -   R₆ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl,        heteroarylalkyl, OR₁₂, and NR₁₃R₁₄;    -   R₇ is selected from OR₁₅, SR₁₅, S(O)R₁₆, SO₂R₁₇, NR₁₃R₁₄, and        NR₁₂SO₂R₆;    -   R₈ is selected from H, OR₁₅, NR₁₃R₁₄, C₁-C₆ alkyl, C₄-C₉        cycloalkyl, C₄-C₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl,        and heteroarylalkyl;    -   R₉ is selected from C₁-C₄ alkyl and C(O)-alkyl;    -   R₁₀ and R₁₁ are the same or different and independently selected        from H, C₁-C₄ alkyl, and —C(O)-alkyl;    -   R₁₂ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, aryl, heteroaryl, arylalkyl, and        heteroarylalkyl;    -   R₁₃ and R₁₄ are the same or different and independently selected        from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,        aryl, heteroaryl, arylalkyl, heteroarylalkyl and amino acyl;    -   R₁₅ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl        and (CH₂)_(m)ZR₁₂;    -   R₁₆ is selected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl        and (CH₂)_(m)ZR₁₂;    -   R₁₇ is selected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl        and NR₁₃R₁₄;    -   m is an integer selected from 0 to 6; and    -   Z is selected from O, NR₁₃, S, S(O),        or a pharmaceutically acceptable salt thereof.

Useful compounds of the formula (II) include those wherein each of R₁,X, Y, R₃, and R₄ is H, including those wherein one of n₂ and n₃ is zeroand the other is 1, especially those wherein R₂ is H or —CH₂—CH₂—OH.

One suitable genus of hydroxamate compounds are those of formula IIa

wherein

-   -   n₄ is 0-3,    -   R₂ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl,        heteroarylalkyl, —(CH₂)_(n)C(O)R₆, amino acyl and —(CH₂)_(n)R₇;    -   R₅′ is heteroaryl, heteroarylalkyl (e.g., pyridylmethyl),        aromatic polycycles, non-aromatic polycycles, mixed aryl and        non-aryl polycycles, polyheteroaryl, or mixed aryl and non-aryl        polyheterocycles,        or a pharmaceutically acceptable salt thereof.

Another suitable genus of hydroxamate compounds are those of formula IIawherein

-   -   n₄ is 0-3,    -   R₂ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl,        heteroarylalkyl, —(CH₂)_(n)C(O)R₆, amino acyl and —(CH₂)_(n)R₇;    -   R₅′ is aryl, arylalkyl, aromatic polycycles, non-aromatic        polycycles, and mixed aryl and non-aryl polycycles; especially        aryl, such as p-fluorophenyl, p-chlorophenyl,        p-O—C₁-C₄-alkylphenyl, such as p-methoxyphenyl, and        p-C₁-C₄-alkylphenyl; and arylalkyl, such as benzyl, ortho, meta        or para-fluorobenzyl, ortho, meta or para-chlorobenzyl, ortho,        meta or para-mono, di or tri-O—C₁-C₄-alkylbenzyl, such as ortho,        meta or para-methoxybenzyl, m,p-diethoxybenzyl,        o,m,p-triimethoxybenzyl, and ortho, meta or para-mono, di or tri        C₁-C₄-alkylphenyl, such as p-methyl, m,m-diethylphenyl,        or a pharmaceutically acceptable salt thereof.

Another interesting genus are the compounds of formula IIb

wherein

-   -   R₂′ is selected from H, C₁-C₆ alkyl, C₄-C₆ cycloalkyl,        cycloalkylalkyl (e.g., cyclopropylmethyl), (CH₂)₂₋₄OR₂₁ where        R₂₁ is H, methyl, ethyl, propyl, and i-propyl, and    -   R₅″ is unsubstituted 1H-indol-3-yl, benzofuran-3-yl or        quinolin-3-yl, or substituted 1H-indol-3-yl, such as        5-fluoro-1H-indol-3-yl or 5-methoxy-1H-indol-3-yl,        benzofuran-3-yl or quinolin-3-yl,        or a pharmaceutically acceptable salt thereof.    -   Another interesting genus of hydroxamate HDAI compounds are the        compounds of formula IIc

wherein

-   -   the ring containing Z₁ is aromatic or non-aromatic, which        non-aromatic rings are saturated or unsaturated,    -   Z₁ is O, S or N—R₂₀,    -   R18 is H, halo, C₁-C₆alkyl (methyl, ethyl, t-butyl),        C₃-C₇cycloalkyl, aryl, for example unsubstituted phenyl or        phenyl substituted by 4-OCH₃ or 4-CF₃, or heteroaryl, such as        2-furanyl, 2-thiophenyl or 2-, 3- or 4-pyridyl;    -   R₂₀ is H, C₁-C₆alkyl, C₁-C₆alkyl-C₃-C₉cycloalkyl (e.g.,        cyclopropylmethyl), aryl, heteroaryl, arylalkyl (e.g., benzyl),        heteroarylalkyl (e.g., pyridylmethyl), acyl (acetyl, propionyl,        benzoyl) or sulfonyl (methanesulfonyl, ethanesulfonyl,        benzenesulfonyl, toluenesulfonyl)    -   A₁ is 1, 2 or 3 substituents which are independently H,        C₁-C-₆alkyl, —OR₁₉, halo, alkylamino, aminoalkyl, halo, or        heteroarylalkyl (e.g., pyridylmethyl), R₁₉ is selected from H,        C₁-C₆alkyl, C₄-C₉cycloalkyl, C₄-C₉heterocycloalkyl, aryl,        heteroaryl, arylalkyl (e.g., benzyl), heteroarylalkyl (e.g.,        pyridylmethyl) and —(CH₂CH═CH(CH₃)(CH₂))₁₋₃H;    -   R₂ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉        heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl,        heteroarylalkyl, —(CH₂)_(n)C(O)R₆, amino acyl and —(CH₂)_(n)R₇;    -   v is 0, 1 or 2,    -   p is 0-3, and    -   q is 1-5 and r is 0 or    -   q is 0 and r is 1-5,        or a pharmaceutically acceptable salt thereof. The other        variable substituents are as defined above.        Especially useful compounds of formula (IIc) are those wherein        R₂ is H, or —(CH₂)_(p)CH₂OH, wherein p is 1-3, especially those        wherein R₁ is H; such as those wherein R₁ is H and X and Y are        each H, and wherein q is 1-3 and r is 0 or wherein q is 0 and r        is 1-3, especially those wherein Z₁ is N—R₂₀. Among these        compounds R₂ is preferably H or —CH₂—CH₂—OH and the sum of q and        r is preferably 1.

Another useful genus of hydroxamate HDAI compounds are the compounds offormula IId

wherein

Z₁ is O, S or N—R₂₀,

R18 is H, halo, C₁-C₆alkyl (methyl, ethyl, t-butyl), C₃-C₇cycloalkyl,aryl, for example, unsubstituted phenyl or phenyl substituted by 4-OCH₃or 4-CF₃, or heteroaryl, R₂₀ is H, C₁-C₆alkyl,C₁-C₆alkyl-C₃-C₉cycloalkyl (e.g., cyclopropylmethyl), aryl, heteroaryl,arylalkyl (e.g., benzyl), heteroarylalkyl (e.g., pyridylmethyl), acyl(acetyl, propionyl, benzoyl) or sulfonyl (methanesulfonyl,ethanesulfonyl, benzenesulfonyl, toluenesulfonyl),A₁ is 1, 2 or 3 substituents which are independently H, C₁-C-₆alkyl,—OR₁₉, or halo, R₁₉ is selected from H, C₁-C₆alkyl, C₄-C₉cycloalkyl,C₄-C₉heterocycloalkyl, aryl, heteroaryl, arylalkyl (e.g., benzyl), andheteroarylalkyl (e.g., pyridylmethyl);p is 0-3, andq is 1-5 and r is 0 orq is 0 and r is 1-5,or a pharmaceutically acceptable salt thereof. The other variablesubstituents are as defined above.Especially useful compounds of formula (IId) are those wherein R₂ is H,or —(CH₂)_(p)CH₂OH, wherein p is 1-3, especially those wherein R₁ is H;such as those wherein R₁ is H and X and Y are each H, and wherein q is1-3 and r is 0 or wherein q is 0 and r is 1-3. Among these compounds R₂is preferably H or —CH₂—CH₂—OH and the sum of q and r is preferably 1.

The present invention further relates to HDAI compounds of the formulaIIe

or a pharmaceutically acceptable salt thereof. The variable substituentsare as defined above.Especially useful compounds of formula (IIe) are those wherein R18 is H,fluoro, chloro, bromo, a C₁-C₄alkyl group, a substituted C₁-C₄alkylgroup, a C₃-C₇cycloalkyl group, unsubstituted phenyl, phenyl substitutedin the para position, or a heteroaryl (e.g., pyridyl) ring.

Another group of useful compounds of formula (IIe) are those wherein R₂is H, or —(CH₂)_(p)CH₂OH, wherein p is 1-3, especially those wherein R₁is H; such as those wherein R₁ is H and X and Y are each H, and whereinq is 1-3 and r is 0 or wherein q is 0 and r is 1-3. Among thesecompounds R₂ is preferably H or —CH₂—CH₂—OH and the sum of q and r ispreferably 1.

Another group of useful compounds of formula (IIe) are those wherein R18is H, methyl, ethyl, t-butyl, trifluoromethyl, cyclohexyl, phenyl,4-methoxyphenyl, 4-trifluoromethylphenyl, 2-furanyl, 2-thiophenyl, or2-, 3- or 4-pyridyl wherein the 2-furanyl, 2-thiophenyl and 2-, 3- or4-pyridyl substituents are unsubstituted or substituted as describedabove for heteroaryl rings; R₂ is H, or —(CH₂)_(p)CH₂OH, wherein p is1-3; especially those wherein R₁ is H and X and Y are each H, andwherein q is 1-3 and r is 0 or wherein q is 0 and r is 1-3. Among thesecompounds R₂ is preferably H or —CH₂—CH₂—OH and the sum of q and r ispreferably 1.

Those compounds of formula IIe wherein R₂₀ is H or C₁-C₆alkyl,especially H, are important members of each of the subgenuses ofcompounds of formula IIe described above.

N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamideandN-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof, are important compoundsof formula (IIe).

The present invention further relates to the HDAI compounds of theformula IIf

or a pharmaceutically acceptable salt thereof. The variable substituentsare as defined above.

Useful compounds of formula (IIf) are include those wherein R₂ is H, or—(CH₂)_(p)CH₂OH, wherein p is 1-3, especially those wherein R₁ is H;such as those wherein R₁ is H and X and Y are each H, and wherein q is1-3 and r is 0 or wherein q is 0 and r is 1-3. Among these compounds R₂is preferably H or —CH₂—CH₂—OH and the sum of q and r is preferably 1.

N-hydroxy-3-[4-[[[2-(benzofur-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof, is an important compoundof formula (IIf).

The above described HDAI compounds and the preparation thereof aredescribed in WO 02/22577 published on Mar. 21, 2002. The specific HDAIcompounds disclosed in WO 02/22577 are herein incorporated by reference.

Other HDAI compounds useful in the practice of the present invention arefor example CI-994, the cyclic depsipeptide FK228 (formerly known as“FR901228”), MS-275 (formerly known as “MS-27-275”), SAHA, Sodiumvalproate, Pyroxamide, Phenyl butyrate, compounds 26 and 27, Prolifixand Apicidin (for chemical structures see below).

HDAI compounds used in the combination of the present invention aretypically those which have an IC₅₀ of less than 2 μM, especially of lessthan 500 nM, and most preferably of less than 100 nM in the histonedeacetylase inhibition assay described in Example B2 of WO 02/22577.

In a first aspect, the present invention relates to a combination, suchas a combined preparation or a pharmaceutical composition, whichcomprises (a) a COX-2 inhibitor, especially the COX-2 inhibitorsmentioned hereinbefore, in particular those mentioned as beingpreferred, and (b) an HDAI, especially the HDAIs mentioned hereinbefore,in particular those mentioned as being preferred, in which the activeingredients (a) and (b) are present in each case in free form or in theform of a pharmaceutically acceptable salt, for simultaneous,concurrent, separate or sequential use.

The term “a combined preparation” defines especially a “kit of parts” inthe sense that the combination partners (a) and (b) as defined above canbe dosed independently or by use of different fixed combinations withdistinguished amounts of the combination partners (a) and (b), i.e.,simultaneously, concurrently, separately or sequentially. The parts ofthe kit of parts can then, e.g., be administered simultaneously orchronologically staggered, that is at different time points and withequal or different time intervals for any part of the kit of parts. Theratio of the total amounts of the combination partner (a) to thecombination partner (b) to be administered in the combined preparationcan be varied, e.g. in order to cope with the needs of a patientsub-population to be treated or the needs of the single patient whichdifferent needs can be due to the particular disease, severity of thedisease, age, sex, body weight, etc. of the patients.

Most preferably, the present invention relates to a combination of (a) aCOX-2 inhibitor which is 5-methyl-2-(2′-chloro-6′-fluoro-anilino)-phenylacetic acid, or a pharmaceutically acceptable salt thereof, and (b) anHDAI selected from the group consisting ofN-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamideandN-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,and pharmaceutically acceptable salts thereof. Preferably, the HDAI isN-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamideor a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the present invention relates to acombination of the present invention for use in the treatment of adisease such as especially pre-malignant colon lesions or a colon canceror other malignancies, preferably pre-malignant colon lesions or a coloncancer, in a mammal, particularly a human.

Other malignancies to be treated according to the present invention arepreferably selected form the group consisting of breast cancer, lungcancer, ovarian cancer, lymphoma, head and neck cancer and cancer of theesophagus, stomach, bladder, prostrate, uterus and cervix.

In the context of the present invention the terms “treatment” or “treat”refer to both prophylactic or preventative treatment as well as curativeor disease modifying treatment, including treatment of patients at riskof contracting the disease or suspected to have contracted the diseaseas well as patients who are ill or have been diagnosed as suffering froma disease or medical condition.

Within the context of this disclosure, any reference to a COX-2inhibitor or an HDAI is understood to include said compounds in theirfree form or as pharmaceutically acceptable salts or any crystal formsthereof including hydrates or solvates, if not indicated otherwise andwhere appropriate and expedient.

In another aspect, the present invention relates to the use of a COX-2inhibitor, especially the COX-2 inhibitors mentioned hereinbefore, inparticular those mentioned as being preferred, or a pharmaceuticallyacceptable salt thereof, for the preparation of a medicament, for use incombination with an HDAI, especially the HDAIs mentioned hereinbefore,in particular those mentioned as being preferred, or a pharmaceuticallyacceptable salt thereof, for the treatment of pre-malignant colonlesions or a colon cancer or other malignancies, preferablypre-malignant colon lesions or a colon cancer, in a mammal, particularlya human.

The present invention also relates to the use of an HDAI, especially theHDAIs mentioned hereinbefore, in particular those mentioned as beingpreferred, or a pharmaceutically acceptable salt thereof, for thepreparation of a medicament, for use in combination with a COX-2inhibitor, especially the COX-2 inhibitors mentioned hereinbefore, inparticular those mentioned as being preferred, or a pharmaceuticallyacceptable salt thereof, for the treatment of pre-malignant colonlesions or a colon cancer or other malignancies, preferablypre-malignant colon lesions or a colon cancer, in a mammal, particularlya human.

In a further aspect, the present invention relates to pharmaceuticalcompositions comprising (a) one or more unit dosage forms of a COX-2inhibitor, especially the COX-2 inhibitors mentioned hereinbefore, inparticular those mentioned as being preferred, or a pharmaceuticallyacceptable salt thereof, and (b) one or more unit dosage forms of anHDAI, especially the HDAIs mentioned hereinbefore, in particular thosementioned as being preferred, or a pharmaceutically acceptable saltthereof, together with at least one pharmaceutically acceptable carrier.

The invention also relates to the use of a combination of the presentinvention for the preparation of a pharmaceutical composition for thetreatment of pre-malignant colon lesions or colon cancer or othermalignancies, preferably pre-malignant colon lesions or a colon cancer,in a mammal, particularly a human.

In another aspect, the present invention relates to a method of treatingpre-malignant colon lesions or a colon cancer or other malignancies,preferably pre-malignant colon lesions or a colon cancer, in a mammal,particularly a human, which comprises treating the mammalsimultaneously, concurrently, separately or sequentially withpharmaceutically effective amounts of (a) a COX-2 inhibitor, especiallythe COX-2 inhibitors mentioned hereinbefore, in particular thosementioned as being preferred, or a pharmaceutically acceptable saltthereof, and (b) an HDAI, especially the HDAIs mentioned hereinbefore,in particular those mentioned as being preferred, or a pharmaceuticallyacceptable salt thereof.

The present invention further relates to a commercial package or productcomprising (a) a COX-2 inhibitor, especially the COX-2 inhibitorsmentioned hereinbefore, in particular those mentioned as beingpreferred, or a pharmaceutically acceptable salt thereof, and (b) anHDAI, especially the HDAIs mentioned hereinbefore, in particular thosementioned as being preferred, or a pharmaceutically acceptable saltthereof, together with instructions for simultaneous, concurrent,separate or sequential use thereof in the treatment of a disease such asespecially pre-malignant colon lesions or a colon cancer or othermalignancies, preferably pre-malignant colon lesions or a colon cancer,in a mammal, particularly a human.

The present invention also relates to a commercial package or productcomprising a COX-2 inhibitor, especially the COX-2 inhibitors mentionedhereinbefore, in particular those mentioned as being preferred, or apharmaceutically acceptable salt thereof, together with instructions foruse in combination with an HDAI, especially the HDAIs mentionedhereinbefore, in particular those mentioned as being preferred, or apharmaceutically acceptable salt thereof, for the treatment of a diseasesuch as especially pre-malignant colon lesions or a colon cancer orother malignancies, preferably pre-malignant colon lesions or a coloncancer, in a mammal, particularly a human,

ora commercial package or product comprising an HDAI, especially the HDAIsmentioned hereinbefore, in particular those mentioned as beingpreferred, or a pharmaceutically acceptable salt thereof, together withinstructions for use in combination with a COX-2 inhibitor, especiallythe COX-2 inhibitors mentioned hereinbefore, in particular thosementioned as being preferred, or a pharmaceutically acceptable saltthereof, for the treatment of a disease such as especially pre-malignantcolon lesions or a colon cancer or other malignancies, preferablypre-malignant colon lesions or a colon cancer, in a mammal, particularlya human.

According to the present invention, a patient is treated withtherapeutically effective amounts of a COX-2 inhibitor and an HDAI inorder to treat pre-malignant colon lesions, such as polyps, or coloncancer, or another malignancy, each according to a dosage regimen thatis appropriate for the individual agent. For example, the COX-2inhibitor may be administered once or more daily and the HDAI may beadministered once daily, on alternate days or on some other schedule—asis appropriate for the HDAI agent when used without the COX-2 inhibitor.One of skill in the art has the ability to determine appropriatepharmaceutically effective amounts of the combination components.

The COX-2 inhibitors and the HDAIs can be prepared and administered asdescribed in the art such as in the documents cited above. If they areavailable on the market they can be administered for example in the formas marketed.

In the instance where the COX-2 inhibitor is5-methyl-2-(2′-chloro-6′-fluoro-anilino)-phenyl acetic acid, or apharmaceutically acceptable salt thereof, and the mammal is a human, anappropriate dose of 5-methyl-2-(2′-chloro-6′-fluoro-anilino)-phenylacetic acid is in the range from 100 to 1500 mg daily, for example,200-1000 mg/day, such as 200, 400, 500, 600, 800, 900 or 1000 mg/day,administered in one or two doses daily. Preferably,5-methyl-2-(2′-chloro-6′-fluoro-anilino)-phenyl acetic acid, or apharmaceutically acceptable salt thereof, is administered as an oralpharmaceutical formulation in the form of a tablet, capsule or syrup.

The following Examples illustrate the invention described above; theyare not, however, intended to limit the scope of the invention in anyway. The beneficial effects of the methods, compositions andcombinations disclosed herein can also be determined by other testmodels known as such to the person skilled in the pertinent art.

EXAMPLES

The short forms and abbreviations used have the following definitions:

AcOH acetic acidaq. aqueousDMSO dimethyl sulfoxideequiv. equivalent(s)Et ethylEtOAc ethyl acetateGC gas chromatographyHPLC high performance liquid chromatographyMeOH methanolTFA trifluoroacetic acidTHF tetrahydrofuran

Example 1 Preparation of[2-(2′-chloro-6′-fluoro-phenylamino)-5-methyl-phenyl]acetic acid

A mixture of 20 g of1-(2′-chloro-6′-fluorophenyl)-5-methyl-1,3-dihydro-indol-2-one, 266 mlof ethanol and 11 ml of water is heated to reflux. 24 g of a 30%solution of sodium hydroxide is slowly added and reflux is continued for1 hour. The solution is cooled to 40-45° C. and treated slowly with asolution of 18 g of concentrated hydrochloric acid in 94 g of deionizedwater up to a pH of 3-4. The obtained suspension is cooled to 20-25° C.and the crystalline material is collected by filtration, washed withethanol/deionized water and dried under reduced pressure to yield 19.5 gof pure [2-(2′-chloro-6′-fluoro-phenylamino)-5-methyl-phenyl]aceticacid. Melting point: 152-154° C.

¹H-NMR (DMSO-d⁶, 500 MHz, 300K) δ 2.21 (s, 3H, CH₃), 3.64 (s, 2H, CH₂);6.42 [dd, J=8.0 Hz, J_(H-F)=3.0, 1H, HC(6)], 6.90 [dd, J=8.0, 2.0 Hz,1H, HC(5)], 7.01 [d, J=2.0 Hz, 1H, HC(3)], 7.09 (s, 1H, NH), 7.09 [ddd,J=8.5 Hz, J_(H-F)=5.5, 1H, HC(4′)], 7.23 [ddd, J=8.5, 1.5 Hz,J_(H-F)=11.0, 1H, HC(5′)], 7.34 [ddd, J=8.5, 1.5 Hz, J_(H-F)=1.5, 1H,HC(3′)], 12.67 (s, 1H, COOH).

Step 1.1A: Preparation of(2′-chloro-6′-fluorophenyl)-(4-methylphenyl)-amine

14.65 g (100 mmol) of 2-chloro-6-fluorophenol are dissolved in 50 ml of2-propanol followed by the addition of 15.5 g (112 mmol) of potassiumcarbonate and 18.9 g (103 mmol) of 2-chloro-N-(4-methylphenyl)acetamide.The mixture is refluxed for 4 hours. At this time, the formation of2-(2′-chloro-6′-fluorophenoxy)-N-(4-methylphenyl)acetamide is completed.20 ml of sodium methylate solution 30% in methanol are slowly added. Tomaintain a temperature of at least 75° C., about 25 ml of solvent aredistilled during the addition. The mixture is boiled 2 hours more tocomplete the formation of(2′-chloro-6′-fluorophenyl)-(4-methylphenyl)-amine.

Then 15 ml of solvent is distilled and 35 ml of water is added to obtaina two phases solution. The lower layer is discarded. The upper layer isdiluted with 35 ml of heptane and washed with 3×25 ml of water. Theorganic phase is separated and concentrated in vacuo to obtain 21.8 g ofcrude oil (2′-chloro-6′-fluorophenyl)-(4-methylphenyl)-amine. Thiscompound (HPLC purity 92%) is used without purification in the next step(Step 1.2).

¹H-NMR (DMSO-d⁶, 500 MHz, 300K) δ 2.17 (s, 3H, CH₃); 6.53 [dd, J=8.5 Hz,J_(H-F)=1.5, 2H, HC(2) and HC(6)], 6.94 [d, J=8.0 Hz, 2H, HC(3) andHC(5)], 7.16 [ddd, J=8.0 Hz, J_(H-F)=6.0, 1H, HC(4′)], 7.25 [ddd, J=8.0,1.5 Hz, J_(H-F)=8.0, 1H, HC(5′)]; 7.34 [ddd, J=8.0, 1.5 Hz, J_(H-F)=1.5,1H, HC(3′)]; 7.63 (s, 1H, NH).

MS (EI) m/z 235 (100, M⁺), 200 (35, (M-Cl)⁺), 185 (55)

Preparation of Starting Material 2-chloro-6-fluorophenol

A solution of 12.1 g (108 mmol) of 2-fluorophenol, 70 mg ofdiisopropylamine and 400 ml of hexane-fraction is heated to 60-65° C.

4 g (56 mmol) of chlorine is introduced at this temperature. Then 60.5 g(540 mmol) of 2-fluorophenol are dropped in the solution over about 2hours, while at the same rate 42 g (590 mmol) more chlorine isintroduced. After that 4 g more chlorine are introduced to complete thechlorination.

GC check: 91% of 2-chloro-6-fluorophenol

-   -   5.2% of 4-chloro-6-fluorophenol    -   3.5% of 2,4-dichloro-6-fluorophenol

200-250 ml of solvent are distilled at normal pressure. The resultingconcentrated solution is slowly cooled to 0-5° C. The obtained thicksuspension is stirred at this temperature for 1 hour, washed with coldhexane-fraction and dried at room temperature.

Yield: 78 g white crystals. GC 99.7%. Melting point: 63.5-64.5° C.

MS (EI) m/z 146 (100, M⁺), 126 [19, (M-HF)⁺]

¹H-NMR (DMSO-d⁶, 500 MHz, 300K) δ 6.8 [ddd, J=8.2 Hz, J_(H-F)=5.5, 1H,HC(4)], 7.15 [m, 2H, HC(3) and HC(5)], 10.3 (s, 1H, OH).

Preparation of Starting Material 2-chloro-N-(4-methylphenyl)acetamide

To a stirred mixture of 34.5 g (322 mmol) of p-toluidine, 100 ml oftoluene and 100 ml of water are added at 20-25° C. from two separateddropping funnels 42.3 g (375 mmol) of chloroacetylchloride and 39 ml ofconcentrated sodium hydroxide 30% at such a rate to maintain a pH of8-12. The obtained suspension is cooled to 0-5° C. The crystallinecompound is filtered, washed with water and cold toluene and dried.

Yield: 55 g HPLC>99%.

Step 1.1B: Alternative preparation of(2′-chloro-6′-fluorophenyl)-(4-methylphenyl)-amine

A mixture of 2-bromo-1-chloro-3-fluorobenzene (32 g, 153 mmol),p-toluidine (16.4 g, 153 mmol), sodium tert.butylate (27.5 g, 286 mmol),(±)-BINAP [2,2′-Bis-(diphenylphosphino)-1,1′-binaphthalin, 0.66 g, 1.1mmol) and toluene (250 ml) is stirred under nitrogen for about 30minutes. After the addition of Palladium-bis-(dibenzylidenaceton) (0.8g, 1 mmol), the mixture is heated to 110° C. (slight reflux) for 14-20hours. The mixture is then cooled to 30° C., water (60 ml), concentratedhydrochloric acid (60 ml) as well as charcoal and cellite (5 g each) areadded and stirring is continued for an hour. The mixture is filtered andthe filtrate is separated into the phases. The organic phase is washedwith water (3 times, 70 ml each) and concentrated in vacuo to obtain37.2 g of crude (2′-chloro-6′-fluorophenyl)-(4-methylphenyl)-amine. Theproduct can be used in the next step (Step 1.2) as such; alternativelyin can be kugelrohrdistilled in vacuo.

Step 1.1C: Alternative preparation of(2′-chloro-6′-fluorophenyl)-(4-methylphenyl)-amine

A mixture of 2-chloro-6-fluoroaniline (4.00 g, 27.5 mmol),4-bromotoluene (4.70 g, 27.5 mmol), sodium tert-butylate (4.75 g, 49.4mmol), and toluene (55 mL) is stirred at 25° C. under nitrogen for 30minutes. To this mixture, a solution ofpalladium-bis-(dibenzylidenacetone) (15.8 mg, 55 mmol) andtri-tert-butylphosphine (1) (8.3 mg, 0.04 mmol) in toluene (5 mL) isadded and the resulting suspension is stirred at 110° C. for 14 hours.The mixture is then cooled to 30° C. Water (30 ml), concentratedhydrochloric acid (10 ml), charcoal and cellite (1 g each) are added andstirring is continued for 1 hour. The mixture is filtered and thefiltrate is separated into its phases. The organic phase is washed threetimes with water (10 mL) and concentrated in vacuo to give 6.5 g ofcrude (2′-chloro-6′-fluorophenyl)-(4-methylphenyl)-amine. The productcan be used directly in the next step (Step 1.2). Alternatively, it canbe distilled in vacuo by Kugelrohr.

Step 1.2: Preparation of2-chloro-N-(2′-chloro-6′-fluorophenyl)-N-(4-methylphenyl)acetamide

20.4 g of crude (2′-chloro-6′-fluorophenyl)-(4-methylphenyl)-amine areheated to about 80° C. and treated with 10.75 g of chloroacetylchloride.The mixture is stirred for 2 hours and diluted with 10 ml of 2-propanol.The solution is cooled to 35-40° C. and seeded. The precipitatedsuspension is diluted with 30 ml of hexane, cooled to 0-5° C. andstirred for about 1 hour. The crystals are isolated by filtration,washed with a cold solution of 2-propanol/hexane ⅓. After drying, 22.7 gof 2-chloro-N-(2′-chloro-6′-fluorophenyl)-N-(4-methylphenyl)acetamideare obtained. HPLC purity: 99%. Melting point: 79-80° C.

¹H-NMR (DMF-d⁷, 400 MHz, 393K) δ 2.44 (s, 3H, CH₃); 4.32 (s, 2H, CH₂),7.35 [d, J=8.0 Hz, 2H, HC(3) and HC(5)], 7.43 [ddd, J=8.0, 2.0 Hz,J_(H-F)=8.0, 1H, HC(5′)], 7.48 [d, J=8.0 Hz, 2H, HC(2) and HC(6)],7.55-[d, J=8.0 Hz, 1H, HC(3′)], 7.60 [ddd, J=8.0 Hz, J_(H-F)=5.5, 1H,HC(4′)].

Step 1.3: Preparation of1-(2′-Chloro-6′-fluorophenyl)-5-methyl-1,3-dihydro-indol-2-one

A melt of 124.8 g (400 mmol) of2-chloro-N-(2′-chloro-6′-fluorophenyl)-N-(4-methylphenyl)acetamide at100-120° C. is treated with 69.3 g (520 mmol) of aluminium chloride insmall parts. The mixture is heated to 160° C. and stirred for 4-6 hoursat this temperature.

The molten mixture is cooled to 110° C. and diluted with 300 ml oftoluene. The obtained solution is added to 500 ml of water at 60° C. Theorganic phase is separated while hot, decolorized with activated carbon,filtered and concentrated. The residue is dissolved in hot 2-propanol,decolorized again with activated carbon, filtered and concentrated to avolume of about 250 ml. The obtained suspension is cooled to 0-5° C.,filtered, washed with cold 2-propanol. After drying, 87 g of1-(2′-chloro-6′-fluorophenyl)-5-methyl-1,3-dihydro-indol-2-one areobtained. Melting point: 137.5-138.5° C.

¹H-NMR (DMSO-d⁶, 500 MHz, 300K) δ 2.27 (s, 3H, CH₃); 3.83 (s, 2H, CH₂);6.35 [d, J=8.0 Hz, 1H, HC(7)], 7.01 [d, J=8.0 Hz, 1H, HC(6)], 7.19 [s,1H, CH(4)], 7.52 [ddd, J=8.5, 2.0 Hz, J_(H-F)=10.0, 1H, HC(5′)], 7.60[ddd, J=8.5, 2.0 Hz, J_(H-F)=1.5, 1H, HC(3′)], 7.63 [ddd, J=8.5 Hz,J_(H-F)=1.5, 1H, HC(4′)].

Example 2 Preparation ofN-Hydroxy-3-[4-[[[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide

4-Formylcinnamic acid methylester is produced by adding 4-formylcinnamicacid (25 g, 0.143 mol) in MeOH and HCl (6.7 g, 0.18 mol). The resultingsuspension is heated to reflux for 3 hours, cooled and evaporated todryness. The resulting yellow solid is dissolved in EtOAc, the solutionwashed with saturated NaHCO₃, dried (MgSO₄) and evaporated to give apale yellow solid which is used without further purification (25.0 g,92%). To a solution of tryptamine (16.3 g, 100 mmol) and4-formylcinnamic acid methylester (19 g, 100 mmol) in dichloroethane,NaBH(OAc)₃ (21 g, 100 mmol) is added. After 4 hours the mixture isdiluted with 10% K₂CO₃ solution, the organic phase separated and theaqueous solution extracted with CH₂Cl₂. The combined organic extractsare dried (Na₂SO₄), evaporated and the residue purified by flashchromatography to produce3-(4-{[2-(1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoicacid methyl ester (29 g). A solution of KOH (12.9 g 87%, 0.2 mol) inMeOH (100 mL) is added to a solution of HONH₂.HCl (13.9 g, 0.2 mol) inMeOH (200 mL) and a precipitate results. After 15 minutes the mixture isfiltered, the filter cake washed with MeOH and the filtrate evaporatedunder vacuum to approximately 75 mL. The mixture is filtered and thevolume adjusted to 100 mL with MeOH. The resulting solution 2M HONH₂ isstored under N₂ at −20° C. for up to 2 weeks. Then3-(4-{[2-(1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoicacid methyl ester (2.20 g, 6.50 mmol) is added to 2 M HONH₂ in MeOH (30mL, 60 mmol) followed by a solution of KOH (420 mg, 6.5 mmol) in MeOH (5mL). After 2 hours dry ice is added to the reaction and the mixture isevaporated to dryness. The residue is dissolved in hot MeOH (20 mL),cooled and stored at −20° C. overnight. The resulting suspension isfiltered, the solids washed with ice cold MeOH and dried under vacuum,producingN-Hydroxy-3-[4-[[[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide(m/z 336 [MH⁺]).

Example 3 Preparation ofN-Hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide

A solution of3-(4-{[2-(1H-indol-3-yl)-ethylamino]-methyl}phenyl)-(2E)-2-propenoicacid methyl ester (12.6 g, 37.7 mmol),(2-bromoethoxy)-tert-butyldimethylsilane (12.8 g, 53.6 mmol),(i-Pr)₂NEt, (7.42 g, 57.4 mmol) in DMSO (100 mL) is heated to 50° C.After 8 hours the mixture is partitioned with CH₂Cl₂/H₂O. The organiclayer is dried (Na₂SO₄) and evaporated. The residue is chromatographedon silica gel to produce3-[4-({[2-(tert-butyldimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-(2E)-2-propenoicacid methyl ester (13.1 g). A solution of KOH (12.9 g (87% pure), 0.2mol) in MeOH (100 mL) is added to a solution of HONH₂.HCl (13.9 g, 0.2mol) in MeOH (200 mL) and a precipitate results. After 15 minutes themixture is filtered, the filter cake washed with MeOH and the filtrateevaporated under vacuum to approximately 75 mL. The mixture is filteredand the volume adjusted to 100 mL with MeOH. The resulting solution 2MHONH₂ is stored under N₂ at −20° C. for up to 2 weeks. Then3-[4-({[2-(tert-butyldimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-(2E)-2-propenoicacid methyl ester (5.4 g, 11 mmol) is added to 2 M HONH₂ in MeOH (90 mL,180 mmol) followed by a solution of KOH (720 mg (87% pure), 11.2 mmol)in MeOH (5 mL) and the mixture stirred overnight. Dry ice is added tothe reaction and the mixture diluted with H₂O resulting in the formationof a precipitate. The liquid was decanted and the solid was dissolved inMeOH and filtered. The filtrate is evaporated to affordN-hydroxy-3-[4-({[2-(tert-butyldimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-(2E)-2-propenamide(5.1 g) which is used without further purification. The hydroxamic acid(5.0 g, 13.3 mmol) is then dissolved in 95% TFA/H₂O (59 mL) and heatedto 40-50° C. for 4 hours. The mixture is evaporated and the residuepurified by reverse phase HPLC to produceN-Hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamideas the trifluoroacetate salt (m/z 380 [MH⁺]).

Example 4 Preparation ofN-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide

A suspension of LiAlH₄ (17 g, 445 mmol) in dry THF (1000 mL) is cooledto 0° C. and 2-methylindole-3-glyoxylamide (30 g, 148 mmol) is added inportions over 30 minutes. The mixture is stirred at room temperature for30 minutes and then maintained at reflux for 3 hours. The reaction iscooled to 0° C. and treated with H₂O (17 ml), 15% NaOH (aq., 17 ml) andH₂O (51 ml). The mixture is treated with MgSO₄, filtered and thefiltrate evaporated to give 2-methyltryptamine which is dissolved inMeOH. Methyl 4-formylcinnamate (16.9 g, 88.8 mmol) is added to thesolution, followed by NaBH₃CN (8.4 g) and AcOH (1 equiv.). After 1 hourthe reaction is diluted with NaHCO₃ (aq.) and extracted with EtOAc. Theorganic extracts are dried (MgSO₄), filtered and evaporated. The residueis purified by chromatography to give3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoicacid methyl ester. The ester is dissolved in MeOH, 1.0 M HCl/dioxane(1-1.5 equiv.) is added followed by Et₂O. The resulting precipitate isfiltered and the solid washed with Et₂O and dried thoroughly to give3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoicacid methyl ester hydrochloride. 1.0 M NaOH (aq., 85 mL) is added to anice cold solution of the methyl ester hydrochloride (14.9 g, 38.6 mmol)and HONH₂ (50% aq. solution, 24.0 mL, ca. 391.2 mmol). After 6 hours,the ice cold solution is diluted with H₂O and NH₄Cl (aq., 0.86 M, 100mL). The resulting precipitate is filtered, washed with H₂O and dried toaffordN-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide(m/z 350 [MH⁺]).

Example 5

5-methyl-2-(2′-chloro-6′-fluoro-anilino)-phenyl acetic acid(alternatively named[2-(2′-chloro-6′-fluoro-phenylamino)-5-methyl-phenyl]acetic acid; forthe preparation see Example 1) (“COX”) andN-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide(alternatively named(E)-N-Hydroxy-3-[4-({(2-hydroxy-ethyl)-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-acrylamide;for the preparation see Example 3) (“HDAI”) are tested as single agentsand together as combination therapy in a mouse model of adenomatouspolyposis for the prevention and treatment of intestinal polyps. HDAI isadministered intravenously to the mice at 10 mg/kg in a 5% (w/v)dextrose in water solution, q.d., 3 times per week for three weeks. COXis administered as a dietary admixture at a concentration of 125 ppm. %T/C is the quotient of the mean number of polyps in the treated micedivided by the mean number of polyps in the control mice times 100. Thefollowing results of duplicate experiments are observed:

DRUGS POLYPS ANIMALS Dose Mean Intestinal Polyp % % Body Wt. Dead/Compound Route Regimen (mg/kg) Count (# ± SEM) T/C Change Total Controlfeed ad libitum — 23 ± 2.0 — +8.2 ± 0.1 0/4 COX feed ad libitum 125 ppm14 ± 0.7 60  +10 ± 0.1 0/7 HDAI i.v. 3x/wk 10 mg/kg  12 ± 0.57 52 +3.5 ±0.1 0/7 COX + HDAI feed + i.v. ad 125 ppm +  8 ± 0.27 33 +4.8 ± 0.1 0/7libitum + 3x/ 10 mg/kg wk Control feed ad libitum — 26 ± 0.4 — +16.3 ±0.2  0/4 COX feed ad libitum 125 ppm 12 ± 0.3 46 +8.1 ± 0.2 0/7 HDAIi.v. 3x/wk 10 mg/kg 15 ± 0.3 57 +9.6 ± 0.1 0/7 COX + HDAI feed + i.v. ad125 ppm +  8 ± 0.3 30 +6.7 ± 0.1 0/7 libitum + 3x/ 10 mg/kg wk

Both agents alone cause a statistically significant reduction in thenumber of newly formed intestinal polyps. The combination furtherreduces the number of polyps to a level that is statisticallysignificantly lower than the number of polyps obtained by treatment witheither agent alone. Statistical evaluations are performed using a onetailed Student t-test and all p values are less than 0.01.

1-33. (canceled)
 34. A commercial package or product comprising (a)5-methyl-2-(2′-chloro-6′-fluoro-anilino)-phenyl acetic acid, or apharmaceutically acceptable salt thereof, and (b)N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamideor a pharmaceutically acceptable salt thereof, together withinstructions for simultaneous, concurrent, separate or sequential usethereof in the treatment of a disease in a mammal.
 35. (canceled)
 36. Acommercial package or product comprising a COX-2 inhibitor or apharmaceutically acceptable salt thereof, together with instructions foruse in combination with a histone deacetylase inhibitor, or apharmaceutically acceptable salt thereof, for the treatment of a diseasein a mammal, or a commercial package or product comprising a histonedeacetylase inhibitor, or a pharmaceutically acceptable salt thereof,together with instructions for use in combination with a COX-2inhibitor, or a pharmaceutically acceptable salt thereof, for thetreatment of a disease in a mammal.
 37. (canceled)
 38. The commercialpackage or product of claim 34 comprising instructions for use in thetreatment of pre-malignant colon lesions or a colon cancer or othermalignancies in a mammal. 39-44. (canceled)
 45. The commercial packageor product of claim 38 where said other malignancies are selected fromthe group consisting of breast cancer, lung cancer, ovarian cancer,lymphoma, head and neck cancer and cancer of the esophagus, stomach,bladder, prostrate, uterus and cervix.
 46. The commercial package orproduct of claim 36 comprising instructions for use in the treatment ofpre-malignant colon lesions or a colon cancer or other malignancies in amammal.
 47. The commercial package or product of claim 46 where saidother malignancies are selected from the group consisting of breastcancer, lung cancer, ovarian cancer, lymphoma, head and neck cancer andcancer of the esophagus, stomach, bladder, prostrate, uterus and cervix.